KR0140492B1 - Opioid formulations having extended controlled release - Google Patents

Abstract

The present invention provides a solid release inhibitory oral dosage form comprising a therapeutically effective amount of an opioid analgesic or a salt thereof that provides an extended pain relief period of about 24 hours, wherein the dosage form is a 37 ° C. 900 ml aqueous buffer (pH). Between 12.5 and about 42.5% (weight) of opioid release after 1 hour, from about 25% to about 55% (weight) of opioid release after 2 hours, as measured by the USP paddle method at 100 rpm Providing adequate form in vitro solubility of opioid release from about 45% to about 75% (weight) after 4 hours and greater than 60% (weight) after 8 hours, wherein the in vitro release rate is substantially pH Irrespective of, the dosage form is characterized in that it is selected to obtain the highest plasma level of opioid in vivo about 2 to 8 hours after administration of the dosage form.

Description

Release-Resistant Opioid Formulations

Dilaudid is 1 mg 4mg Graph showing plasma levels when two tablets were administered,

2 is a graphical representation of plasma levels obtained in Example 5,

3 is a graphical representation of plasma levels obtained in Example 6,

4 is a graphical representation of plasma levels obtained in Example 7,

5 is a graphical representation of plasma levels obtained in Example 8,

6 is a graph showing a comparison of plasma levels obtained by Example 5 and Comparative Example A,

7 is a graph showing the plasma levels obtained in Comparative Examples B and C,

8 is a graphical representation of the plasma levels obtained in Examples 9 and 10,

9 is a graph showing the comparison of plasma levels obtained in Examples 11 and 12 with Comparative Example D,

10 is a graphical representation of the plasma levels obtained by Examples 11 and 12 compared to the trough level for Comparative Example D,

11 is a graph showing a comparison between the plasma level obtained in Example 13 and the plasma level obtained in Comparative Example E.

The present invention relates to dosage forms for solid release inhibiting oral administration useful for treating pain.

The purpose of all release-release (sustained release) formulations is to provide a longer duration of drug action after drug administration than would normally be obtained after immediate release of a dosage form. Such long response periods provide a number of therapeutic advantages that cannot be obtained by short acting, immediate release formulations. Thus, the course of treatment can be continued without disturbing the patient's sleep, for example during treatment to alleviate the patient's extreme pain (eg, after surgery, cancer patients, etc.) or in patients with debilitating sleep. Of course, this is especially important for patients who experience migraine headaches during awakening.

In conventional fast-acting pharmacotherapy, the plasma level of the active drug is increased due to the rapid absorption, systematic excretion, and metabolic inactivation of the compound if the drug is not administered carefully and frequently to maintain the fixed plasma level of the drug effectively. Attainment of highs or lows leads to special problems in patient maintenance therapy. Another general advantage of long-acting drug preparation is to improve patient compliance to avoid undosed medications due to patient forgetting.

Morphine is considered a prototypic opioid analgesic and has been formulated in a 12-hour release inhibitory formulation (ie, MS Contin commercially available from Purdue Frederick). refine).

It has been known in the art that release inhibitory compositions of opioids or salts thereof can be prepared in suitable matrices. For example, U.S. Patent Nos. 4,990,341 and 4,844,909 (Goldy et al.), Also assigned to the assignee of the present invention, disclose a hydromorphone composition, wherein the in vitro dissolution rate of the prepared form is 37 ° C 900 ml aqueous buffer (pH). 12.5-42.5% (weight) hydromorphone dissolution after 1 hour, 25-55% (weight) dissolution after 2 hours, measured at 100 rpm within 1.6 to 7.2) according to the USP paddle or bath method. To 75% by weight dissolution and 55 to 85% by weight dissolution after 6 hours. In vitro dissolution rate is independent of pH between pH 1.6 and 7.2 and is chosen such that the highest plasma levels of hydromorphone obtained in vivo appear between 2 and 4 hours after administration of the appropriate form. By the hydromorphone formulation, a pain elimination effect of 12 hours or more is obtained.

It has been another goal in the industry to develop drug formulations that have a duration of drug effect of more than 12 hours and can only be administered once a day, for example.

There is a need for a dosage form of a convenient and reliable opioid analgesic that can be administered less frequently than the currently widely used analgesics. The most widely used oral opioid analgesic formulations are formulated and selected to have a less frequent dose than 12 hours and are administered every 4 to 6 hours. An obvious benefit of once-daily dosage forms is the increased convenience and compliance as reported in detail for many drug formulations where the need for less frequent administration is met.

To date, the less frequent opioid analgesic formulation (a) affects the incidence and / or behavior of drug adverse reactions when compared to the same chemical compound administered in the form of a traditional immediate release oral dosage form at the same daily total dose. (b) There is disagreement that there is a difference between the analgesic efficacy of short-acting oral opioid analgesic formulations and long-acting formulations in terms of the dosage required for a given time. The results of many appropriate and well-controlled double-blind, randomized safety and efficacy assessments have been confirmed in many homologous studies, as long-term and short-acting opioids for long-term and short-acting oral administration occur and produce analgesic effects and side effects at the same daily dose. And the degree is the same.

Simultaneous administration of non-opioid analgesic drugs in combination with opioid-based drugs has demonstrated the opioid-reducing effect of non-opioid analgesics. However, the only previously reported method of reducing opioid demand is in case of patient-controlled analgesia (PCA), which reduces the need for opioid analgesics compared to parenteral administration on demand (PRN). It was only. In this case (PRN), the method of administration is not at regular intervals, but rather as a PRN medication as usual, rather than a PRN using the patient as the primary regulator of drug administration and using PCA and the patient and other populations controlling the timing of the request.

It is an object of the present invention to provide a method and opioid analgesic formulation which substantially improves the efficiency and quality of pain treatment.

Another object of the present invention is to provide a treatment method that substantially improves the efficiency and quality of pain treatment.

It is another object of the present invention to provide a release inhibitory opioid formulation with a significantly increased effect duration compared to conventional release inhibitory opioid formulations.

The above objects and others are achieved by the present invention in connection with a solid release inhibitory dosage form for oral administration, wherein the dosage form of the present invention comprises a therapeutically effective amount of an analgesic agent, preferably an opioid analgesic or a salt thereof Either coated with a coating or present in a release retardant matrix. Wherein the in vitro dissolution rate in the appropriate form is 12.5 to 42.5% (weight) of opioid release after 1 hour as measured by USP paddle or basket method at 100 rpm in 900 ℃ aqueous buffer (pH 1.6-7.2) 37 ℃, 2 hours Followed by 25 to 56% (weight) opioid release, 45 to 85% (weight) opioid release after 4 hours, and about 60% or more opioid release after 8 hours, in vitro release is substantially independent of pH The highest plasma levels of opioids obtained within 2 to 8 hours after dosage administration. The dosage form for oral administration of the present invention may be administered once daily, because it eliminates pain for 24 hours.

As described above the dosage form preferably comprises an opioid analgesic. Preferred opioids include hydromorphone, oxycodone, morphine, levorpanol, methadone, meperidine, heroin, dihydrocodeine, codeine, dihydromorphine, buprenorphine, salts thereof, mixtures of any of the foregoing And mu-caustic opioid analgesics, mu-caustic roots / antagonists, and mu-cranial roots / antagonists.

USP paddle or basket method refers to the paddle and basket method described in US Pharmacopoeia XXII (1990).

The expression substantially independent of pH herein means that the difference between the amount of opioid released at any given pH at any given time, for example pH 1.6, and the amount released at another pH, for example pH 7.2 is 10 It means within% (weight). (Measurement is performed in vitro using USP paddle or basket method at 100 rpm in 900 ml quartz buffer). The amount released is expressed as the average of at least three experimental results in all cases.

The present invention also relates to a method for treating pain in a patient comprising administering a dosage form for oral administration of the present invention.

The solid dosage forms for release oral release of the present invention have surprising results of opioid savings. Firstly, the solid dosage forms for release oral release of the present invention may be administered at a substantially lower daily dosage than conventional immediate release formulations without any difference in analgesic effect. Second, when administered in the same daily dosage, the solid dosage form for the release inhibitory oral administration of the present invention, its efficacy is superior to conventional immediate release products.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT Hereinafter, the present invention will be described in detail with reference to the accompanying drawings.

The present invention provides an inhibitory dosage form of opioid analgesic with an extended therapeutic effect duration (eg, about 24 hours), providing a peak plasma level (ie, Tmax) about 2 to 8 hours after administration. It is based on the surprising finding that the highest plasma levels are provided between about 4 hours and 6 hours after administration such that pain relief lasts for at least 12 hours, preferably about 24 hours after oral administration.

In addition, in the dosage form of the present invention, significant levels of treatment can generally be obtained without a significant increase in the intensity and / or degree of side effects such as vomiting, nausea, or drowsiness, often accompanied by high plasma levels of opioids. There is also evidence to demonstrate that the use of the present dosage forms reduces the risk of drug addiction.

Another advantage of the compositions of the present invention that release opioid analgesics at a constant rate regardless of pH (eg between pH 1.6 and 7.2) is that it can prevent drug dumping upon oral administration.

First, oral opioid analgesics are formulated to prolong the duration of analgesic action so that they can be administered once daily. Surprisingly, these formulations have a lower incidence of side effects at the same dose as the conventional daily release of the immediate release drug and can be administered at lower daily dosages than conventional oral medications during analgesic treatment. Thus, the 24-hour dosage formulations of the present invention may have an opioid-saving effect.

The dosage forms for oral administration of the present invention may be provided, for example, in the form of granules, spheres or tablets in capsules or other suitable solid forms. In a particularly preferred embodiment, the oral dosage form comprises spheres contained in an effective number of capsules.

In one preferred embodiment, the dosage form for oral release of opioid opioids of the present invention comprises as a therapeutically active ingredient hydromorphone and preferably about 4 to 64 mg hydromorphone hydrochloride. Alternatively, the dosage form may comprise equimolar amounts of other hydromorphone salts or hydromorphone bases. In another preferred embodiment where the opioid analgesic is other than hydromorphone, the dosage form contains it in an appropriate amount to provide a substantially equivalent therapeutic effect.

For example, when the opioid analgesic contains morphine, the release inhibitory dosage form of the invention contains from about 15 mg to about 800 mg of morphine.

On the other hand, when the opioid analgesic comprises oxycodone, the release inhibitory dosage form of the present invention comprises from about 10 mg to about 400 mg of oxycodone.

The dosing-response studies and relative analgesic evaluation reports of the muu-causoidal opioid analgesics showed that there was no significant deviation from their parallel relationship. This is very well established and the result is a prediction theory that provides the relative analgesic efficacy factor and dose rates commonly used when switching patients from one muu-driven analgesic to another, regardless of previous formulation.

In one preferred embodiment of the present invention, the release inhibitory dosage form comprises a sphere containing the active ingredient coated with a release inhibiting coating.

The term sphere is known in the pharmaceutical arts and means spherical granules having a diameter between 0.1 mm and 2.5 mm, in particular between 0.5 mm and 2 mm.

The spheres are preferably film coated with a material such that release of opioids (or salts) is inhibited in the aqueous medium. The film coating is selected to achieve the in vitro release rate (such as between 12.5% and 42.5% by weight after one hour of administration), along with other recognized properties. The coating formulations of the present invention must be flexible and precise so that they can support pigments and other coating additives and produce strong continuous films that are nontoxic, inert and free of viscosity.

In one preferred embodiment, the invention comprises an opioid coated with hydrophobic materials selected from ethyl cellulose such as ethylcellulose, acrylic polymers, shellac, zein, hydrophobic waxy products such as hardened castor oil or hardened vegetable oil and mixtures thereof It relates to the solid release inhibitory dosage form of the substrate.

In another preferred embodiment, the coating is derived from an aqueous dispersion of hydrophobic polymer. The coated substrate containing the opioid (eg, tablet core or inert pharmaceutical beads or spheres) is then cured until the substrate reaches a cure endpoint that provides stable dissolution behavior. Curing endpoints can be determined by comparing the appropriate form of dissolution behavior (curves) immediately after exposure to accelerated storage conditions (eg, at least 1 month at a temperature of 40 ° C. and 75% relative humidity). Such formulations are described in detail in co-pending US patent applications Ser. Nos. 07 / 814.111 and 07 / 826.084.

Aqueous dispersions of hydrophobic polymers used as coatings in the present invention may be used in combination with tablets, spheres (or beads), microspheres, seeds, pills, ion exchange resin beads, and other multiparticulate systems to obtain the desired release inhibitory therapeutic agent. Can be. The granules, spheres or tablets produced by the present invention may be provided in capsules or other suitable dosage forms. To obtain an inhibitory formulation, the weight gain is about 2, although the protective coating increases or decreases depending on the physical properties of the therapeutic active, the required release rate, the plasticizer content in the aqueous dispersion and the manner in which it is incorporated. It is always necessary to coat the substrate containing the therapeutically active agent with a sufficient amount of an aqueous acid solution such as ethylcellulose or an acrylic polymer so that it is from 25% to 25%. Although ethylcellulose is one preferred hydrophobic polymer that can be used to coat the substrates of the present invention, those skilled in the art will appreciate that some cellulose polymers, including other alkyl cellulose polymers, are included in some or all of the ethyl cellulose contained in the hydrophobic polymer coating of the present invention. It will be understood that can be replaced.

In another preferred embodiment of the present invention, the hydrophobic polymer constituting the release inhibitory coating is not limited to acrylic acid, but is not limited to methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cinnaoethyl Methacrylate, methyl methacrylate copolymer, methacrylic acid copolymer methyl methacrylate copolymer, methyl methacrylate copolymer, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, Methyl methacrylate copolymer, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamide copolymer, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), methyl methacrylate, Polymethacrylate, methyl methacrylate copolymer, poly (methyl methacrylate), poly (methyl methacrylate) copolymer, polya Reel amide, an aminoalkyl methacrylate copolymer, poly (methacrylic acid anhydride), and glycidyl methacrylate copolymer available pharmaceutically acceptable acrylic polymer, including a polymer.

In certain preferred embodiments, the acrylic polymer consists of one or more amonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art and are disclosed as copolymers in which NF XVII is fully polymerized with acrylic and methacrylic esters and low content of tetravalent ammonium groups.

In order to obtain the desired dissolution behavior it is necessary to mix two or more ammonio methacrylate copolymers with different physical properties, such as different molar ratios of tetravalent ammonium groups, to the neutral (meth) acrylic acid esters.

In embodiments of the invention where the coating comprises an aqueous dispersion of hydrophobic polymer, incorporating an effective amount of plasticizer in the aqueous dispersion of the hydrophobic polymer will further enhance the physical properties of the film. For example, since ethylcellulose has a relatively high glass transition temperature and does not form a flexible film under conventional coating conditions, it is necessary to plasticize ethylcellulose before using ethylcellulose as a coating material. In general, the amount of plasticizer included in the coating solution is based on the concentration of the film-former. For example in most cases about 1-50% by weight of the film former. However, the concentration of plasticizer can only be determined appropriately after careful examination of the specific coating solution and application method.

Examples of suitable plasticizers for ethylcellulose include insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl straight, tributyl citrate, and triacetin, including acetylated monoglycerides, phthalate esters, castors Other water insoluble plasticizers, such as lead, may also be used. Triethyl citrate is a particularly suitable plasticizer for the aqueous dispersion of ethylcellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymer of the present invention include, but are not limited to, citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and 1,2-propylene glycol Include. Eudragit Other plasticizers that have proven to be suitable for increasing the flexibility of films formed from acrylic films such as RL / RS lacquer solutions include polyethylene glycol, propylene glycol, diethyl phthalate, castor oil, and triacetin. Triethyl citrate is a particularly preferred plasticizer for the aqueous acid solution of ethyl cellulose of the present invention.

It has also been found that adding small amounts of talc reduces the sticking tendency of aqueous dispersions during processing and acts as a lubricant.

One commercially available ethyl acid aqueous solution of aquacoat (FMC Corp., Philadelphia, Pennsylvania, USA). Aquacoat Can be prepared by dissolving ethyl cellulose in an organic solvent that cannot be mixed with water and then emulsifying it in water in the presence of a surfactant and a stabilizer. After homogenization to make a sphere of 1 micron or less, the organic solvent is evaporated in vacuo to form pseudolatex. The plasticizer is not mixed into the pseudolatex during the manufacturing process. Therefore, before using such a coating, Aquacoat Needs to be mixed with a suitable plasticizer.

Other aqueous acid solutions of ethyl cellulose are Surelease Commercially available under the trade names (Colorcon, Inc., West Point, Pennsylvania, USA). This product is manufactured by mixing a plasticizer with an aqueous acid solution during the manufacturing process. The hot melt, plasticizer (dibutyl sebacate) and stabilizer (oleic acid) of the polymer are made into a homogeneous mixture and then diluted with alkaline solution to obtain an aqueous acidic solution which can be directly applied to the substrate.

In one preferred embodiment, the acrylic coating is an acrylic resin lacquer used in the form of an aqueous acid solution. (For example Eudragit Commercially available from Rohm Pharma under the tradename.) In another preferred embodiment, the acrylic coating is each Eudragit from Rohm Pharma. RL30D and Eudragit And mixtures of two types of acrylic resin lacquers commercially available under the trade name RS30D. Eudragit RL30D and Eudragit RS30D is a copolymer of acrylic and methacrylic esters containing low content tetravalent ammonium groups, the molar ratio of ammonium groups to residual neutral (meth) acrylic esters being Eudragit 1:20 in RL30D and Eudragit 1:40 in RS30D. The average molecular weight is about 150,000. The code designations RL (high permeability) and RS (low permeability) are indicative of the permeability of these reagents.

Eudragit RL / RS mixtures are insoluble in water and digestive fluids. However, coatings made from such are swellable and permeable in aqueous and digestive solutions.

Eudragit of the present invention The RL / RS dispersion can be mixed in any desired ratio to obtain a release inhibitory formulation that ultimately has the desired dissolution behavior. For example, the preferred release inhibitory formulation is 100% Eudragit RL, 50% Eudragit RL and 50% Eudragit RS, and 10% Eudragit RL: 90% Eudragit It can be obtained from a delayed coating composed of RS. Of course, those skilled in the art It will be appreciated that other acrylic polymers, such as RL, may also be used.

In addition to varying the dissolution behavior by varying the relative amounts of different acrylic resin lacquers, the dissolution behavior of the final product can also be varied by, for example, increasing or decreasing the thickness of the delayed coating.

When an aqueous acidic solution of a hydrophobic polymer is used to coat inert pharmaceutical beads, such as Nu-Pareil 18/20 beads, a plurality of the resulting stabilized solid release inhibitory beads are then ingested into the gelatin capsule and gastric fluid It may be present in an amount sufficient to provide an effective release inhibitory dose when in contact with.

The stabilized release inhibitory formulations of the present invention slowly release the therapeutically active agent when ingested and exposed to gastric juice, followed by intestinal fluid. The release inhibitory behavior of the formulations of the present invention may vary the amount of coating comprising the aqueous dispersion of the hydrophobic polymer, the way plasticizer is added to the aqueous dispersion of the hydrophobic polymer, or the amount of plasticizer relative to the hydrophobic polymer. It can be varied by a method such as changing, adding an additional ingredient or excipient, or modifying the manufacturing method. Spheres or beads coated with a therapeutically active agent are prepared, for example, by dissolving the therapeutically active agent in water and then spraying the solution onto a substrate (eg Nu-Pareil 18/20 beads using a Wurster insert). Optionally, additional ingredients are added prior to coating the beads to assist in binding the hydromorphone to the beads and / or to color the solution.

For example, products containing hydroxypropyl methylcellulose or the like with or without colorant may be added to the solution and mixed before being applied to the beads. (For example, for about an hour). The resulting coated substrate in the beads of the above example may then be optionally coated with a barrier agent to separate the therapeutic active from the hydrophobic release inhibiting coating. Examples of suitable barrier agents are those comprising hydroxypropyl methylcellulose. However, any film-former known in the art may be used. It is desirable that the barrier does not affect the rate of dissolution of the final product.

Hydromorphone, HPMC coated (optionally) beads can then be coated with an aqueous dispersion of hydrophobic polymer. Aqueous dispersions of hydrophobic polymers further comprise an effective amount of plasticizer (eg, triethyl citrate). Aquacoat Or Surelease Pre-formulated aqueous dispersions of ethylcellulose such as can be used. Surelease If is used, there is no need to add a plasticizer separately. Alternatively, Eudragit Pre-formed aqueous dispersions of acrylic resins such as can be used.

The coating solution of the present invention preferably contains a colorant in addition to the film forming agent, the plasticizer, and the solvent system (ie, water) to improve the quality and quality of the product. Colorants may be added to the solution of the therapeutically active agent in place of or in addition to an aqueous dispersion of hydrophobic polymer. For example, the colorant may be made from an alcohol or propylene glycol based colorant dispersion, milled aluminum rake and an opacifier such as titanium dioxide, and the colorant is added to the aqueous polymer solution using shear stress and then plasticized. Aquacoat Aquacoat using low shear stress against Is added to. Alternatively, any method may be used to color the formulations of the present invention. When aqueous dispersions of acrylic polymers are used, suitable as components for imparting colorants to the formulations are colorant pigments such as titanium dioxide and iron oxide pigments and the like. However, the binding of the pigments increases the delay effect of the coating.

Plasticized aqueous dispersions of hydrophobic polymers can be applied onto a substrate containing a therapeutically active agent by spraying using any suitable nebulizer known in the art. In a preferred method, a Wurster fluidization-bed system is used in which air is injected from the bottom while the acrylic polymer coating is sprayed to fluidize and dry the core material.

When the coated substrate is exposed to an aqueous solution such as gastric fluid, an aqueous dispersion of hydrophobic polymer in sufficient amount to obtain a predetermined release inhibitory property of the therapeutic agent is considered in consideration of the physical properties of the therapeutic agent, the method of mixing the plasticizer, and the like. Coating. Opadry after coating with hydrophobic polymer Coatings that are coating agents such as are optionally applied to the beads. Such a coating is provided to significantly reduce at least the aggregation of the beads.

The coated beads are then cured to obtain a stabilized release rate of the therapeutic agent.

To date, attempts to prepare stable release inhibitory pharmaceutical formulations using aqueous dispersions of hydrophobic polymers have not been successful because of stability issues. In particular, it is known to those skilled in the art that the dissolution release behavior changes over time when the pharmaceutical form is coated with an aqueous polymer dispersion to obtain the desired release inhibitory behavior of the active drug for several hours or more.

This problem can be solved by the present invention. In the present invention, an aqueous dispersion of ethyl cellulose is used as the release inhibiting coating, and the curing step is performed by coating the coated substrate (ie ethyl cellulose) until the curing end point is reached. ) At a temperature above the glass transition temperature and relative humidity of about 60% to about 100%.

In a preferred embodiment of the invention, a stabilized product derived from an aqueous dispersion of ethylcellulose is obtained by oven curing the substrate to be coated at elevated temperature and humidity for the required time, at which time the temperature for making the individual formulations is achieved. Optimum values of humidity, humidity and time are determined experimentally. In a particular embodiment of the invention, the stabilized product coated with an aqueous dispersion of ethylcellulose is subjected to oven cure performed for about 48 to 72 hours at a temperature of about 60 ° C. and a humidity of about 60% to about 100%. Obtained. This is the case for hydromorphone beads, which will be described in the Examples below. However, those skilled in the art will understand that the curing conditions required to obtain a stabilized formulation may vary somewhat, and are actually broader than the temperature, humidity and time ranges described above, depending on the individual formulation.

Traditionally, Eudragit Curing of the coated formulation was performed through a fluidized bed at 45 ° C. for 2 hours after application. This standard cure is recommended by Rohm Pharma, which Eudragit said condition is plasticized to 20% solids level by triethyl citrate. This is because the glass transition temperature (Tg) of RS 30 D is higher. This recommended curing does not stabilize the release behavior of the formulation upon storage, which will be demonstrated by the following examples.

This problem can be overcome by the present invention, in which the aqueous dispersion of hydrophobic polymer is Eudragit A stabilized product comprising an aqueous dispersion of acrylic polymer, such as, is carried out at a temperature above the glass transition temperature of the coating formulation, and is substantially unaffected even when the coated formulation is exposed to elevated temperatures and / or humidity storage conditions. It is obtained by oven curing that lasts until the end point is reached which yields dissolution behavior.

In general, the curing time may be, for example, about 24 hours or more, and the curing temperature may be, for example, about 45 ° C. It was further discovered that the coated substrate does not need to be left at humidity levels above atmospheric conditions during the curing process to obtain a stabilized final product.

In a preferred embodiment of the invention, which is an acrylic coating, the stabilized product is obtained by oven curing the substrate to be coated at a temperature above the glass transition temperature (Tg) of the plasticized acrylic polymer for the required time, for each formulation. Optimum temperature and time are determined experimentally. In a particular embodiment of the invention, the stabilized product is obtained by oven curing carried out at a temperature of about 45 ° C. for about 24 to 48 hours.

It is also envisaged that for certain products coated with the release inhibitory coating of the present invention a curing time of at least 24 hours (eg, about 24 to 48 hours, or 60 hours or more) may be required.

The release of the therapeutically active agent from the release inhibitory formulation of the invention can be controlled at a desired rate by adding one or more release-modifying agents, or by providing one or more passageways through the coating. The ratio of hydrophobic polymer to water soluble material is determined by the release rate required among other factors and the dissolution properties of the selected material. The release-modifying agent, which functions as a pore-former, can be organic or inorganic, and can include materials that can be filtered and extracted from the coating and dissolved in the coating in the environment of use. The pore former may comprise one or more hydrophobic polymers such as hydroxy propylmethylcellulose.

The release inhibitory coating of the present invention may also include an erosion-promoting agent such as starch and gum.

The release inhibitory coating of the present invention may also comprise materials useful for forming microporous lamina in the environment of use, such as consisting of linear polyesters of carbonic acid in which carbonate groups repeatedly appear in the polymer chain. Polycarbonate.

The release-modifying agent may also comprise a semipermeable polymer. In certain preferred embodiments, the release-modifying agent is selected from hydroxypropyl methylcellulose, lactose, metal stearate, and mixtures of any of the foregoing.

The release retardant coating of the present invention may comprise an exit means comprising one or more passageways, holes, or the like. The passage may be formed by a method as disclosed in US Pat. Nos. 3,845,770: 3,916,889: 4,063,064 and 4,088,864. The passage may take any shape, such as spherical, triangular, rectangular, elliptical, irregular, and the like.

In another embodiment, the present invention utilizes a release inhibitory matrix that provides in vitro dissolution rates of opioids within the desired narrow range (instead of or in addition to release inhibitory coatings) and allows the release of opioids regardless of pH. Can be. Suitable materials for inclusion in the release inhibitory matrix are

(a) Hydrophilic polymers such as gums, cellulose ethers, acrylic resins and protein-derived materials, of which cellulose ethers are preferred, in particular hydroxy alkylcelluloses and carboxylated celluloses. Suitable dosage forms for oral administration may comprise 1 to 80% by weight of one or more hydrophilic or hydrophobic polymers.

(b) digestible long chains (C ₈ -C ₅₀ , in particular C ₁₂ -C ₄₀ ) such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, minerals and plant fibers and beeswax, substituted or unsubstituted hydrocarbons, 25 ° and Hydrocarbons having a melting point between 90 ° C. are preferred. Of these long-chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred. Suitable dosage forms for oral administration may include up to 60% (by weight) of one or more digestible long chain hydrocarbons.

(c) Polyalkylene glycols, oral dosage forms for oral administration may comprise up to 60% by weight of one or more polyalkylene glycols.

One particularly suitable matrix comprises one or more water soluble hydroxyalkylcelluloses, one or more C ₁₂ -C ₃₆ , preferably C ₁₄ -C ₂₂ , aliphatic alcohols and optionally one or more polyalkylene glycols. Preference is given to at least one of the hydroxyalkyl celluloses described above, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, in particular, hydroxy (C ₁ to C ₆ ) alkylcelluloses such as hydroxy ethylcellulose.

The amount of one or more hydroxyalkylcelluloses in the oral dosage form of the present invention is determined in particular by the exact release rate of the opioid required. One or more aliphatic alcohols described above may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. However, in a particularly preferred embodiment of the oral dosage form of the invention, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. The amount of one or more aliphatic alcohols described above in the dosage form for oral administration of the present invention is determined by the exact release rate of the opioid required as described above. It also depends on whether or not one or more polyalkylene glycols are present in oral dosage form. If no one or more polyalkylene glycols are present, the dosage form for oral administration includes between 20% and 50% (weight) of one or more aliphatic alcohols. When one or more polyalkylene glycols are present in the dosage form for oral administration, the sum of the weights of the one or more aliphatic alcohols and the one or more polyalkylene glycols constitutes between 20% and 50% (weight) of the total amount.

In a preferred dosage form of the invention, for example, the ratio of one or more hydroxy alkylcelluloses or acrylic resins to one or more aliphatic alcohols / polyalkylene glycols determines the release rate of opioid from the formulation to a significant extent. The ratio of one or more hydroxy alkylcelluloses to one or more aliphatic alcohols / polyalkylene glycols is preferably between 1: 2 and 1: 4, more preferably between 1: 3 and 1: 4.

One or more polyalkylene glycols can be for example polypropylene glycol, preferably polyethylene glycol. The number average molecular weight of the at least one polyalkylene glycol is preferably between 1000 and 15000, in particular between 1500 and 12000.

Other suitable release inhibitory matrices may include alkylcelluloses (especially ethylcellulose), C ₁₂ to C ₃₆ aliphatic alcohols and optionally polyalkylene glycols.

In addition to the above components, the release inhibitory matrix may include or include other materials in suitable amounts, such as, for example, diluents, lubricants, binders, granulating aids, pigments, fragrances and lubricants commonly known in the art.

In order to facilitate the preparation of the solid release inhibitory oral dosage form according to the present invention, the solid release inhibitory oral dosage form according to the present invention is characterized by including an opioid or a salt thereof in the release inhibitory matrix. Methods of preparation are provided in another aspect of the present invention. The process of inclusion in the matrix is

(a) forming a granule comprising at least one water soluble hydroxyalkyl cellulose and an opioid or opioid salt,

(b) mixing at least one hydroxyalkyl cellulose containing granule with at least one C ₁₂ -C ₃₆ aliphatic alcohol, and

(c) optionally by compacting and shaping the granules. Preferably the granules are formed by wet granulating hydroxyalkyl cellulose / opioid with water. In a particularly preferred embodiment of this process, the amount of water added in the wet granulation step is between 1.5 and 5 times the dry weight of the opioid, particularly preferably between 1.75 and 3.5 times.

In another embodiment, a spheronizing agent together with the active ingredient can be spheronized to form spheres. Microcrystalline cellulose is preferred. Suitable microcrystalline cellulose is for example a material sold by Avicel PH 101 (trademark, FMC Corporation). In this embodiment the spheres may also comprise a binder, in addition to the active ingredient and spherical aids. Suitable binders, such as low viscosity, water soluble polymers, will be well known to those of ordinary skill in the pharmaceutical arts. However, water soluble hydroxy low alkylcelluloses such as hydroxypropyl cellulose are preferred. Further (or alternatively) the spheres may comprise water-insoluble polymers, in particular acrylic polymers, acrylic copolymers such as methacrylic acid-ethylacrylate copolymer, or ethyl cellulose. In this embodiment, the release inhibiting coating is generally

(a) wax, alone or mixed with fatty alcohol

(b) Shellac or Zein

Water insoluble materials such as;

Inhibitory release opioid formulations of the invention are detailed below according to the examples.

The following examples illustrate various aspects of the present invention. It is noted that in any way this does not limit the scope of the claims.

Example 1

Release-Resistant Hydromorphone

Hcl 8mg Formulation-Acrylic Polymer Coating

Example 1 was prepared as follows:

Drug Loading

Hydromorphone Hcl was dissolved in water and Opadry Y5-1442 (hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, polyethylene glycol and DC Red No. 30 aluminum, commercially available from Colorcon, West Point, PA). Hydromorphone beads were prepared by adding a light pink product comprising a lake) and then mixing to obtain a 20% w / w suspension for about 1 hour. This suspension was then sprayed onto Nu-Pareil 18/20 mesh beads using Wurster inserts.

2. Primary coating

The laminated hydromorphone beads were coated with a Wurster insert to increase 5% w / w with Opadry Light Pink. This coating was applied as a protective coating.

3. Coating of delay coating

After primary coating, the hydromorphone was coated with a 5% weight increase with a delayed coating mixture of Eudragit RS 30D and Eudragit RL 30D (RS: RL = 90: 10). Triethyl citrate (plasticizer) and talc (antistick) were also included in the Eudragit suspension. Wurster inserts were used when applying the coating suspension.

4. Secondary coating

When the coating of the delayed coating was finished, the hydromorphone beads were coated with a 5% weight increase with Opadry Light Pink using a Wurster insert. This coating was also applied as a protective coating.

5. Curing

After the final coating was finished, the hydrophone was cured in a 45 ° C. oven for 2 days. Cured beads were then filled into gelatin capsules at 8 mg hydromorphone concentration. The complete composition of the beads prepared by Example 1 is shown in Table 1 below.

Dissolution tests were performed on both the initial formulation of the Eudragit coated hydromorphone beads of Example 1 and the formulation after 28 days and the results are shown in Table 2 below.

As shown in Table 2 above, the stability test of Eudragit-coated hydromorphone beads shows that the initial dissolution of the beads is the same as the dissolution performed on the sample placed at 37 ° C./80% RH conditions.

Example 2-4

Release-Resistant Hydromorphone

Hcl 8mg Formulation-Ethylcellulose Coating

Example 2-4 was prepared as follows:

1. Drug Loading

After dissolving hydromorphone Hcl in water, Opadry Y5-1442, Light Pink (hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, polyethylene glycol, and DC Red No. 30 aluminum lake, were included in Colorcon, West Hydromorphone beads were prepared by adding Point, a commercially available product from PA) and then mixing to obtain a 20% w / w suspension for 1 hour. This suspension was then sprayed onto Nu-Pareil 18/20 mesh beads using Wurster inserts.

2. Primary coating

The laminated hydromorphone beads were coated with a Wurster insert to increase 5% w / w with Opadry Light Pink. This coating was applied as a protective coating and gave immediate release hydromorphone beads. See Table 3 below:

3. Coating of delay coating

After primary coating, the hydromorphone beads were retarded coating consisting of Aquacoat ECD 30 and triethyl citrate (plasticizer) based on the dry weight of the Aquacoat at 5% (Example 2), 10% (Example 3). ), And 15% (Example 4) coated to increase weight.

Coating suspensions were coated using Wurster inserts.

4. Curing

After coating the delayed coating, the beads were placed in a 60 ° C. oven equipped with accompaniment to maintain a relative humidity of 85% and allowed to cure for 72 hours.

5. Secondary coating

The cured beads were removed from the humidifying oven and dried in a fluidized bed dryer for about 1 hour. The dried cured beads were coated using a Wurster insert with a 5% w / w increase in Opadry Light Pink. This coating is coated with a protective coating.

The final compositions of beads with 5%, 10% and 15% Aquacoat coatings, respectively, are shown in Tables 4, 5 and 6, respectively.

7. Encapsulation

The hydromorphone beads were filled into hard gelatin capsules such that the total amount of hydromorphone Hcl per capsule was 8 mg using the following composition:

Example 2 All Beads Retain 5% Aquacoat Coatings;

Example 3: 75% with a 10% Aquacoat coating and the remaining 25% were immediate release beads;

Example 4 75% of beads have 15% Aquacoat coating and 25% of immediate release beads.

Dissolution tests were performed on both the initial formulation of the Aquacoat coated hydromorphone beads of Examples 2-4 and the formulation after 28 days and the results are shown in Tables 7-9 below.

The stability experiments of Aquacoat-coated hydromorphone beads of Examples 2-4 show that, as described above, the initial dissolution is the same as that performed at 37 ° C./80% RH conditions.

Example 5-8

In Examples 5-8, one dose randomized crossover test (one week lost) was performed on 12 patients in six ways and compared with the results obtained for equivalent doses of immediate release formulations. Blood samples are taken immediately after administration of 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 48 hours to determine plasma levels. Measured. Comparative Example A is an 8 mg hydromorphone immediate release formulation (two Dilaudid ^R 4 mg tablets commercially available from Knoll). Example 5 is an 8 mg dose of the encapsulated hydromorphone beads of Example 1. Example 6 is an 8 mg dose of the encapsulated hydromorphone beads of Example 2. Example 7 is an 8 mg dose of the encapsulated hydromorphone beads of Example 3. Example 8 is an 8 mg dose of the encapsulated hydromorphone beads of Example 4.

The results obtained for Comparative Example A are shown in FIG. The results obtained for Example 5 are shown in FIG. The results obtained for Example 6 are shown in FIG. The results obtained for Example 7 are shown in FIG. The results obtained for Example 8 are shown in FIG. FIG. 6 shows the results for Comparative Example A versus the plasma levels of Example 5. The results for Examples 5-8 are shown in Tables 10 and 11 below. They provide data on the area under the curve (bioavailability), peak plasma concentration (C _max ), and time to reach peak plasma level (T _max ).

With regard to Example 7, the following conclusions can be made. The bioavailability of Example 7 was 88%. Tolerable levels of agencies such as the FDA are:

Example 7 has a reduced C _max that corresponds to one half of Comparative Example A; And

For Comparative Example A, it has a T _max of 2.39 hours as opposed to a T _max of 1.1 hours. Dilaudid is known to be valid for about six hours. As confirmed through FIG. 1, at 6 hours the plasma level of 8 mg Dilaudid was about 300 pg / ml hydromorphone. Thus, a circulation concentration of about 300 pg / ml is an effective analgesic concentration in plasma.

In contrast, the results obtained for Example 5 showed that plasma levels of hydromorphone exceeded 500 pg / ml hydromorphone at 12 hours post-dose, and plasma levels exceeded 300 pg / ml 24 hours after dosing. Shows. Thus, it can be seen that this product is suitable for once-daily administration and is an opioid-saving formulation.

Example 7, on the other hand, provides a plasma level of 300 pg / ml after 12 hours of administration and a plasma level of 250 pg / ml after 24 hours of administration. However, the dose of hydromorphone administered in Example 7 was only 8 mg every 24 hours. In contrast, the total dosage for the same time period, to maintain the analgesic effect using the immediate release formulation, would be 16 mg (4 mg every 6 hours).

As shown in FIG. 4, when two capsules of Example 7 were administered, it was clear that the trough or trough concentration would exceed the 300 pg / ml level in 24 hours. The two tablets of Example 7 will be in the same dosage as the immediate release formulation for 24 hours. However, the amount of beads included in the final formulation can be adjusted to provide a final formulation with a substantially 24 hour dosage than the immediate release formulation in the same period. Thus Example 7 is considered an opioid saving formulation. Therefore, this product is suitable for once-daily administration.

Example 9-10

In Example 9-10, a single dose randomized crossover test was conducted in four ways on 10 subjects. Example 9 was an 8 mg dose of the hydromorphone beads of fasting-Example 5; In contrast, Example 10 was administered post-prandial hydromorphone (2 Dilaudid 4 mg tablets) on an empty stomach. 8 mg of immediate release hydromorphone (2 Dilaudid 4 mg tablets) in Comparative Example C was administered after meals.

Plasma levels of Comparative Examples B and C are shown in FIG. 7 and plasma levels for Examples 9 and 10 are shown in FIG. The results of Examples 9-10 and B and C are shown in Table 12. Table 12 provides data for the area under the curve, and the percent immediate uptake (bioavailability), peak plasma concentration (C _max ), and time to peak plasma concentration (T _max ) compared to immediate release.

Table 12

Group AUC% IRT _max C _max

Example 9210591014.91259

Example 10258331064.61721

Comparative Example B209091000.853816

Comparative Example C244601001.153766

As confirmed from the results provided by Examples 9-10 and Comparative Examples B and C, there was a minimal food effect on both the immediate release tablets and the inhibitory beads of Examples 9 and 10, and Example 9 And bioavailability for 10 release inhibitory beads was slightly increased. From the plasma levels it can be confirmed once again that this product is suitable for once-daily administration and twice daily administration. At 24 hours, the release product provided a plasma level of nearly 600 pg / ml and at 12 hours, a plasma level exceeding 700 pg / ml.

Examples 11-12

In Examples 11-12, the stationary crossover test was performed in three ways for 4 days. In Comparative Example D, 8 mg immediate-release hydromorphone (2 Dilaudid 4 mg tablets) was administered to the subject every 6 hours. In Example 11, 82 mg of the hydromorphone beads of Example 5 were administered every 12 hours. In Example 12, 8 mg of the hydromorphone beads of Example 5 were administered every 24 hours. Blood samples were taken on day 4.

The plasma levels in Comparative Example D relative to the plasma levels in Examples 11 and 12 are shown in FIG. Trough levels of Comparative Example D to plasma levels in Examples 11 and 12 are shown in FIG. 10. In FIG. 10, the value for Example 12 was doubled. The results for Examples 11-12 and Comparative Example D are shown in Table 13 below. Table 13 provides data on the percentage of absorption (bioavailability), peak plasma concentration (C _max ), and time to peak plasma concentration (T _max ) compared to the lower curve area and immediate release.

Table 13

Group AUCACUC * T _max C _max C _max ^*

Example 1162223275955.534752232

Example 1239233288794.827302189

Comparative Example D47835222361.031242163

AUC * = 0-12 hours for Q12H 0-24 hours for Q24H and 0-12 hours for Q6H

C _max ^* = C _max- 0 si figures

From the data in Table 13 in relation to the curve area (AUC), which is a measure of bioavailability, it can be seen that Comparative Examples D, Examples 11 and 12 all show the same AUC increase during the dosing interval, indicating that all dosage forms are bioavailable. To indicate.

Furthermore, in this test, the dose of 16 mg per day was doubled via Example 12, administered at 8 mg every 14 hours (this amount is 4 mg every 6 hours for immediate release formulations). If the same amount of hydromorphone) is provided, this formulation is an excellent 24-hour preparation. The trough and bone concentrations shown in FIG. 10 for Example 12 show that this product is equivalent to a 4 mg immediate release formulation (administered every 6 hours), resulting in an excellent once daily dose product.

Example 13

Release-Resistant Morphine Sulfate

30mg Formulation-Acrylic Polymer Coating

Example 13 was prepared in the same manner as in Example 1. Example 13 The overall composition of the beads is shown in Table 14 below.

Table 14

Drug loading

Ingredient amount / mono

Morphine Sulfate Powder 30.0 mg

Anhydrous lactose 42.5 mg

Povidone 2.5 mg

Nupareil PG 18/20 25.0 mg

Pure qs

Opadry Red YS-1-1841 10.5 mg

Pure qs

Delay coating

Eudragit RS30D 10.3 mg

Eudragit RS30D 0.2 mg

Triringethyl citrate 2.1 mg

Talc 2.9 mg

Pure qs

2nd coating

Opadry Red Ys-1-1841 12.0 mg

Pure qs

Total 239.3 mg

The ratio of Eudragit RS30D to Eudragit RL30D is 98: 2. After completion of the final coating the morphine beads were cured in a 45 ° C. oven for 2 days. The cured beads were then filled into 30 mg concentrations in gelatin capsules.

The dissolution test for Eudragit coated morphine of Example 13 was carried out initially and after 3 months under accelerated storage conditions and the results are shown in Table 15 below.

Table 15

Storage Conditions Dissolution Melt

% Dissolved time (hours)

Test period 1 2 4 8 12

Initial 2.624.760.589.498.8

40 ° C / 75% RH5.827.362.089.889.1 after 1 month

After 3 months 40 ℃ / 75% RH6.826.565.387.695.1

The dissolution behavior of Example 13 shown in Table 15 shows that Example 13 is stable.

A double-blind one-dose crossover test was then performed on 12 subjects with respect to the dosage form of Example 13 relative to the standard formulation of Comparative Example E.

In Comparative Example E, a commercially available release inhibitory morphine sulfate tablet (MS Contin ^R available from Purdue Frederick) was administered.

The results are shown in FIG. 11 by plotting the plasma levels of the double dose of Example 13 relative to the plasma levels obtained by Comparative Example E. FIG.

The above embodiments are not meant to be exclusive. Many variations of the invention will be apparent to those of ordinary skill in the pharmaceutical arts and are predictable within the scope of the appended claims.

Claims (11)

A solid release inhibitory oral dosage form comprising an analgesic effective amount of an opioid analgesic or salt thereof coated with a release inhibitory coating or dispersed in a release inhibitory matrix, the dosage form being 39 ° C. 900 ml aqueous buffer (pH 1.6 and Between 7.2 and about 42.5% (weight) of opioid release after 1 hour, and from about 25% to about 65% (weight) of opioid release after 2 hours, as measured by the USP paddle method at 100 rpm. Provided in dosage form in vitro solubility of opioid release from about 45% to about 85% (weight) after time and greater than 60% (weight) after 8 hours, the rate of in vitro release being substantially dependent on pH Solid release inhibitory oral administration, characterized in that it is selected to obtain the highest plasma level of opioid in the body at about 2 to 8 hours after the dosage form. Q.s. form. The method of claim 1, The opioid analgesic is from the group consisting of hydromorphone, oxycodone, morphine, levorfanol, methadone, meperidine, heroin, dihydrocodeine, codeine, dihydromorphine, butrenorphine, salts thereof and mixtures thereof Suitable form, characterized in that the selected. The method of claim 1, The dosage form is characterized in that the dosage form contains an effective amount of the spheres comprising the opioid analgesic or a salt thereof and coated with a release inhibitory coating. The spheres are coated with a pharmaceutically acceptable hydrophobic material selected from the group consisting of alkylcelluloses, acrylic polymers, shellacs, zeins, hardened castor oils, hardened vegetable oils and mixtures of any of the foregoing Appropriate form. The method of claim 4, wherein The dosage form, wherein the hydrophobic material is coated on the sphere with an aqueous dispersion. The method according to any one of claims 1 to 5, An appropriate dosage form, wherein said opioid analgesic consists of about 4 mg to about 64 mg of hydromorphone. The method according to any one of claims 1 to 5, The dosage form, wherein said opioid analgesic consists of about 15 mg to about 800 mg of morphine. The method of claim 7, wherein The dosage form is characterized in that the hydrophobic material is selected from the group consisting of alkylcellulose, acrylic polymers, shellac, zein, hardened castor oil, hardened vegetable oil and mixtures of any of these. The method according to any one of claims 1 to 5, The dosage form, wherein said opioid analgesic consists of about 10 mg to 400 mg of oxycodone. The method according to any one of claims 1 to 5, The dosage form, wherein the dosage form provides a peak in vivo plasma level of the opioid between about 4 hours and 6 hours after administration. The method according to claim 1 or 2, The dosage form is characterized in that the dosage form is in the form of a release inhibitory matrix.